Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 6, Issue 1, 2008

Pharmacogenetics has made its entrance in psychiatry since the discovery of the first polymorphism directly correlated to individual variability in Cytochrome P450 (CYP) metabolism. Currently, most of the major drugmetabolizing CYP enzymes, their specific CYP-drug relationships and many of their gene variants are known. This has led to the development of elegant models predicting individualized dose recommendations. This has however not yet resulted in a widespread implementation of CYP genotyping in daily practice, mainly due to unfamiliarity and lack of prospective data. Recently it has been shown that therapeutic drug monitoring with additional CYP genotyping improved the treatment with antidepressants of patients in the general practice setting. Considerable effort has been put into developing a FDA approved DNA microarray, identifying multiple clinical relevant CYP polymorphisms at once. This could pave the way for a wide implementation of pharmacogenetic testing in the clinical environment. Individual variability in drug response is not explained by variation of drug metabolism alone. Polymorphisms in neurotransmitter-receptor genes are gaining more interest since they are at the end of the line in determining psychotropic drug effects. Several studies have already shown that the response of antipsychotic drugs and antidepressants can be predicted by genotyping polymorphisms in serotonin receptors and transporter genes. The increased predictability of the different determinants in drug efficacy brings us a step closer to personalized medicine in psychiatry.

Pharmacogenetics (PGt) is a fast evolving field in medical science, since adverse drug reactions (ADR) and therapy failure may be due to variations in the genes of drug metabolizing enzymes, drug transporters and drug targets. There are many different techniques available for the detection of mutations, Single Nucleotide Polymorphisms (SNPs) and gene copy number variations (CNVs) that allow the scientist to apply the best suited method for defined diagnostic questions. This article reviews some of the most important genes of pharmacogenetic relevance, gives an overview of several methods frequently used for genotyping and provides insight into routine pharmacogenetic testing in the clinical laboratory.

Genomics is becoming the integral part of Pharmacogenomics, and the Paired-End diTag (PET) technology is creating a new paradigm in Genomics. The PET technology directly links the 5' terminal tags of cDNAs or genomic sequences with their corresponding 3' terminal tags to form PET ditags and concatenates them for efficient sequencing. The GIS (Gene Identification Signature)-PET analysis was developed for studying transcriptomes and pathway aberrations. It can precisely demarcate the alternative transcription start site (TSS) and the alternative polyadenylation site (PAS). The paired-end nature makes the identification of fusion genes, fusion transcripts, and pseudogenes very straightforward. Additionally, PET-associated genes can be correlated to pathway database to systematically reveal global pathway aberrations. Changes in metabolic and signal transduction pathways can be compared across different cell types. Later, the ChIP (Chromatin immunoprecipitation)-PET analysis was developed. This approach facilitates genome-wide mapping of transcription factor binding sites (TFBSs), as shown in the studies of p53, c-Myc, estrogen receptor, Oct4/Nanog/Sox2, STAT1, NFκB. In addition, study of trimethylations of lysine4 and lysine27 in H3 histone protein demonstrated the capability of ChIP-PET for genome-wide mapping of epigenetic modifications. Integration of all these PET data would produce a comprehensive picture of genetic and epigenetic cis-acting elements, gene expression and regulation, and pathway activities; and data can be analyzed and compared at molecular, gene, and pathway levels. This article reviews the advancement of the PET technology and discusses its potential applications in Pharmacogenomics.

Thiopurine drugs azathioprine and 6-mercaptopurine are inactive compounds that must be metabolized to 6- thioguanine nucleotides to exert their immunosuppressive properties. Hypoxanthine-guanine phosphoribosyltransferase anabolizes 6-mercaptopurine into the 6-thioguanine nucleotides responsible for the therapeutic activity and drug-related leucopenia. On the other hand, thiopurine methyltransferase (TPMT) metabolizes 6-mercaptopurine into inactive methylmercaptopurine. Therefore, reduction in TPMT activity predisposes to bone marrow suppression because of preferential metabolism of 6-mercaptopurine to 6-thioguanine nucleotides. The choice of the dose of azathioprine/6-mercaptopurine is generally based on the patient's weight. However, several strategies have been suggested in choosing, in a more individualized and safer way, the thiopurine dose, with the intention, on one hand, to identify patients at risk of myelotoxicity and, on the other hand, to detect patients with inadequate immunosuppressant. In this respect, quantification of TPMT activity has been considered a promising area, as it may identify unique metabolic profiles in patients at high risk for adverse reaction prior to drug exposure. The aim of the present manuscript is to review the following aspects related with TPMT determination: 1) TPMT activity distribution in general population. 2) Advantages and disadvantages of TPMT genotype and phenotype determination. 3) Relationship between TPMT activity and azathioprine induced myelotoxicity. 4) TPMT activity and immunosuppressive efficacy of azathioprine. 5) How can azathioprine dose be adjusted based on TPMT activity? 6) Is TPMT activity monitoring indicated in all patients who are going to receive azathioprine? 7) Can systematic blood controls be avoided in patients treated with azathioprine if TPMT is determined?

There are a number of effective treatments for breast cancer in the neo-adjuvant, adjuvant and metastatic setting. These comprise combinations of radiotherapy, chemotherapy, hormonal treatments and targeted molecular therapies. However the benefit that individual patients derive from these treatments and the toxicity that they experience varies considerably. Differences in cancer patient's responses to therapy can be associated with factors such as disease burden, drug interactions, age, gender and nutritional status amongst others. It is now also known that genetic variations in drug target genes, disease pathway genes and drug metabolizing enzymes can have important role and influence on the efficacy and toxicity of a particular therapy. These genetic variations may be due to variations in individual's germ line DNA or to somatic changes in the malignant cells. Understanding the genetic profile of the patient and the tumour will help to further refine therapies. Pharmacogenomics can be used to predict response to treatments that are known to have activity against breast cancer including anthracyclines, cyclophosphamide, methotrexate, fluorouracil, taxanes, tamoxifen, aromatase inhibitors and herceptin. The reliability and reproducibility of techniques needs to be validated in large randomized studies before they can be incorporated into routine clinical practice. Thus pharmacogenomics will help develop a profile to tailor therapies with minimal toxicity and maximum efficacy based on molecular signatures. This review discusses clinically relevant germ line mutations that can be used to predict response and toxicity to the above treatments as well as microarray based expression profile studies that may yield important information about prognosis, indication for treatment and response to treatment. The completion of the human genome project and advances in high through-put DNA sequencing and proteomic technology means that there is a real opportunity for pharmacogenomic assessment to become a clinically important part of the decision making process in determining the optimum adjuvant treatment regimen for patients with early stage breast cancer and aiding the management of advanced breast cancer, allowing clinicians to create an individual management plan for each breast cancer patient based on pharmacogenomic data.

The primary goal of immunosuppressive treatment after organ transplantation is to optimize its benefit/risk ratio in order to have the best combination of efficacy and tolerability. Tacrolimus (Tc), Sir (SRL), cyclosporine (CsA) and mycophenolic acid based drugs are characterized by a narrow therapeutic index and broad interindividual variability in their pharmacokinetic parameters. Their bioavailability is affected by a range of factors including absorption, distribution, biotransformation and elimination, resulting in considerable disparity in drug safety and efficacy profiles. Therapeutic monitoring is becoming a crucial component of routine practice to maintain time-dependent target concentrations. Recently, special interest in polymorphisms in genes encoding biotransformation enzymes and drug transporters has opened promising new perspectives for the selection of individual dosages. Several single nucleotide polymorphisms (SNP) have been identified in both CYP3A4 and CYP3A5 as well as in UGT genes encoding metabolizing enzymes, and in ABCB1 and ABCC2 genes encoding membranous transporters. A particular SNP within intron 3 of the CYP3A5 gene has been shown to generate production of a truncated protein associated with the CYP3A5*3 allele and expression of the active CYP3A5 enzyme with its CYP3A5*1 allele. The functional significance of this SNP has been confirmed with respect to Tc in the stable phase after kidney, liver, heart and lung transplantation. The same effect is also seen in the early phase after kidney transplantation, even following initial administrations of the drug. The influence of the CYP3A5 SNP in intron 3 is less marked in case of CsA administration, and however, was recently demonstrated for SRL disposition in some circumstances. Findings on the contribution of ABCB1 SNPs to interindividual variability in blood levels of immunosuppressive drugs remain contradictory. Prospective studies are still needed to prove that a genetic approach, in association with therapeutic drug monitoring, may enhance efficacy and safety, both in the short and long term after transplantation.

Several lines of evidence indicate that apolipoprotein E (apoE) plays a central role in the brain's response to injury and neurodegeneration in the adult. The coordinated expression of apoE and several of its accessory proteins appears to regulate the transport and internalization of cholesterol and phospholipids during development and normal brain reinnervation in the adult. The discovery, a few years ago, that a genetic variant in the apoE gene called apoE4 strongly links to both sporadic and familial late onset Alzheimer's disease (AD) has raised the possibility that a dysfunction of the lipid transport system in the brain could be central to AD pathophysiology. Pathophysiological evidence obtained in autopsyconfirmed sporadic AD cases clearly indicate that the presence of apoE4 allele in humans directly compromises cholinergic function in the adult brain and indirectly modulate the efficacy of medications designed to enhance the cholinergic activity in diseased brain. The apoE4 allele was found to significantly increase the risk of progression to dementia for persons exhibiting amnestic mild cognitive impairment (aMCI), a transitional state between the cognitive changes associated with normal aging and early AD. Furthermore, two accessory enzymes involved in cholinergic neurotransmission called butyrylcholinesterase and paraoxonase-1 were shown i) to display polymorphic variants that increase the risk of developing AD and ii) to modulate drug responsiveness in AD subjects exposed to cholinomimetic agents. This article reviews the most critical findings in this field and reassess the potent clinical value of pharmacogenomics of neurodegenerative diseases and dementia.